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Would you prescribe metformin or let primary care handle that? Here are several articles on metformin, which together put more pressure on us to either prescribe it or assure that it’s being aggressively considered and managed by another team member.
Hi! Jim Phelps here for the Psychopharmacology Institute. Officially, this Quick Take is about metformin for patients taking clozapine, but let’s look at metformin more broadly. You wouldn’t likely be surprised to hear that among patients starting clozapine, those who were also given metformin or were already on it had less weight gain than the clozapine-alone group. But you might not expect the numbers at 1 year. No weight gain at all in the clozapine-metformin group vs a 4.7 kg increase for clozapine alone.
A 2016 meta-analysis found that metformin was more effective in preventing antipsychotic-induced weight gain in first-episode patients than in patients who’d already gained weight, and that weight gain can happen fast. One study found that the average weight gain in the first 3 months of antipsychotic treatment was 3.5 kg. So, if you’re going to prescribe metformin, the data suggest you should do it very early, maybe even starting it almost concomitantly with antipsychotics that are also notorious for weight gain like olanzapine, risperidone, and quetiapine. But many psychiatrists are understandably hesitant to prescribe metformin. It’s a scope of practice issue and a relationship with primary care issue. And of course, there are nonmedication alternatives for weight control and those should be vigorously used with good motivational interviewing.
Well, here’s another prod toward getting your weight management act together—the TRIO-BD study. This is a randomized trial of metformin in treatment-resistant bipolar depression. It’s small and it needs replication, but the implications are huge. This study was led by Dr. Cynthia Culkin, a former primary care physician who later trained in psychiatry. She and her colleagues’ hypothesis was that insulin resistance contributes to treatment resistance in bipolar depression. All 45 research participants in this study had insulin resistance as defined by fasting glucose and insulin levels, and the authors compared outcomes for patients who converted, who no longer met criteria for insulin resistance, vs nonconverters. Half the patients randomized to metformin converted vs 1 patient on placebo.
Among the converters, depression scores on the Montgomery-Asberg Depression Rating Scale or the MADRS were significantly lower at 6 months, with an effect size of 1.5. That’s huge. Interestingly, anxiety scores on the Hamilton Anxiety Scale were also significantly lower for the converters, with an effect size of 1.0.
Now, this is a preliminary trial. There were only 11 converters. Nevertheless, I hope it’s making you think about how to manage weight gain with your patients. Imagine that if by inducing insulin resistance, we also induce treatment resistance, at least in bipolar depression. That’s an iatrogenic disaster.
One more finding that might be reassuring as you contemplate using metformin for patients at risk of metabolic syndrome. In Dr. Culkin’s study, loose stool was the most common side effect in 40% of the metformin group. This was also present in 32% of the placebo group, which was not statistically different from the metformin group—nor was any other side effect, including nausea or vomiting, statistically more common in the metformin group.
For more on this, perhaps it’s time to review the prescribing information on metformin if you’re not already routinely using it.
Abstract
Objective: Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain.
Methods: We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes.
Results: Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only.
Conclusion: In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.
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Reference
Stogios, N., Maksyutynska, K., Navagnanavel, J., Sanches, M., Powell, V., Gerretsen, P., Graff-Guerrero, A., Chintoh, A. F., Foussias, G., Remington, G., Hahn, M. K., & Agarwal, S. M. (2022).
Acta Psychiatrica Scandinavica,
10.1111/acps.13462. Advance online publication.
